A5102833678- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Computational Drug Discovery Methods
- DNA Repair Mechanisms
- Microtubule and mitosis dynamics
- Heat shock proteins research
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Cancer-related Molecular Pathways
- Microbial Natural Products and Biosynthesis
- Fungal and yeast genetics research
- Ubiquitin and proteasome pathways
- Enzyme Production and Characterization
- Biochemical and Structural Characterization
- Melanoma and MAPK Pathways
- Parkinson's Disease Mechanisms and Treatments
- Biochemical and Molecular Research
- Cell death mechanisms and regulation
- Down syndrome and intellectual disability research
- Fungal Biology and Applications
- Toxin Mechanisms and Immunotoxins
Granta Design (United Kingdom)
2009-2021
Institute of Cancer Research
2007
Cancer Research UK
2007
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe structure-based design, synthesis, structure−activity relationships and pharmacokinetics potent small-molecule inhibitors based on 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity Hsp90, measured in a fluorescence polarization (FP) competitive binding assay, active cancer cell lines where they inhibit proliferation exhibit...
We describe our work to establish structure- and fragment-based drug discovery identify small molecules that inhibit the anti-apoptotic activity of proteins Mcl-1 Bcl-2. This identified hit series compounds, some which were subsequently optimized clinical candidates in trials for treating various cancers. Many protein constructs designed with suitable properties different biophysical assays structural methods. Fragment screening using ligand-observed NMR experiments several compounds each...
Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 domain based on checkpoint 1 (CHK1) mutants were designed, expressed insect cells infected baculovirus, purified, and crystallized. X-ray structures surrogates complexed known inhibitors rationalized compound potency selectivity. The CHK1 10-point mutant was preferred, following assessment surrogate binding affinity inhibitors....
The serine/threonine kinase DYRK1A has been implicated in regulation of a variety cellular processes associated with cancer progression, including cell cycle control, DNA damage repair, protection from apoptosis, differentiation, and metastasis. In addition, elevated-level activity increased severity symptoms Down's syndrome. A selective inhibitor could therefore be therapeutic benefit. We have used fragment structure-based discovery methods to identify highly selective, well-tolerated,...
Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-d]pyrimidines underwent optimization using X-ray structures LRRK2 domain surrogates, based on checkpoint 1 (CHK1) a CHK1 10-point mutant. (2R)-2-Methylpyrrolidin-1-yl derivative 18 (LRRK2 G2019S cKi 0.7 nM, LE 0.66) was identified, with increased potency consistent an structure 18/CHK1 10-pt. mutant showing the 2-methyl...
Abstract Conventional chemotherapeutic agents such as gemcitabine, cisplatin or irinotecan induce DNA damage and activate cell cycle checkpoints. P53 defective tumors lack a functional G1 checkpoint rely heavily on the S G2 checkpoints, effector kinase Chk1, for protection against this damage. Inhibiting Chk1 potentiates anti-tumor effects of these cytotoxic agents. Targeting is potential therapeutic opportunity potentiating efficacy damaging drugs without increasing their toxicity to normal...
Abstract Pin1 is a peptidyl-prolyl isomerase (PPIase) that specialized for catalysing isomerization around pSer/Thr-Pro bonds. As isomerisation such bonds can promote major conformational changes within proteins, able to influence signaling dynamics and outcomes pathways regulated by proline-directed kinases as: MAP kinases, cyclin-dependent GSK-3β. overexpression only weakly oncogenic in itself, but enhances transformation ErbB2 or activated Ras alleles. Remarkably however, cells from...
Abstract On sustaining damage to their DNA, cells employ a sophisticated mechanism of detection and repair, termed the DNA response (DDR). As critical component DDR G2/M checkpoint, Chk1 kinase represents an attractive target for cancer therapy. We have utilized structure-based drug design approach identify develop VER-250840, novel, orally active inhibitor checkpoint kinase, Chk1. VER-250840 exhibited sub-nM potency against with exquisite selectivity over extensive diverse panel kinases. In...